The Pharmacokinetics of Antiepileptics Drugs in Neonates with … · 2017. 8. 5. · Seizures in...

The Pharmacokinetics of

Antiepileptics Drugs in

Neonates with Hypoxic

Ischemic EncephalopathyKELIANA O’MARA, PHARMD

FLORIDA NEONATAL NEUROLOGIC NETWORK STATE MEETING

Objectives

Describe seizures in hypoxic ischemic encephalopathy

Review the pharmacology of anti-epileptic drugs (AEDs) used in neonates

Discuss literature for AEDs in neonatal hypoxic ischemic encephalopathy

Seizures in HIE

HIE remains one of the most common underlying etiologies for neonatal seizures1

Incidence is 22-64% using routine EEG or aEEG

Seizures correlate with biomarkers of brain injury

Majority are subclinical—punctuates need for EEG

Limited data regarding occurrence during therapeutic hypothermia (TH)

Much of earlier literature predates routine use of TH

Questions remain on relationship between hypothermia and incidence/timing of seizures in neonates

with HIE

No reliable clinical markers predict which babies undergoing TH will seize2

1. Wusthoff et al. J Child Neurol 20112. Boylan et al. Sem in Fet Neonatal Medicine 2015

Escobar M et al 2011

Seizures in HIE undergoing

Hypothermia

It appears overall incidence of seizures remains unchanged with the

introduction of hypothermia

Seizure profile has been altered

Lower overall seizure burden, shorter individual seizure durations, seizures that

are harder to detect

Seizure burden in neonates with moderate HIE who undergo hypothermia

is lower than normothermic neonates

Seizure burden in neonates with severe HIE treated with hypothermia do

not differ between normothermic and hypothermic neonates

Boylan et al. Seminars in Fetal & Neonatal Medicine 2015

Seizures in HIE and Neurodevelopment

Long-term outcome in generally poor when both conditions are present1

Debate exists over whether seizures themselves cause additional damage

to the neonatal brain or if they represent a manifestation of existing brain

injury

Animal data suggest addition of seizures can have further detrimental

effects

Some neonatal data suggest worsening neurodevelopmental outcomes

with seizures in the setting of birth asphyxia independent of HIE severity2

1. Kwon et al. J Child Neurol 20112. Glass et al. J Pediatr 2009

Seizures in the Neonatal Period

Neonatal brain is more susceptible to seizures

Early development of excitatory neurotransmitters

Delayed inhibitory function of GABA

Excess of excitatory glutamatergic neurons with more excitable subunits than

the adult brain

GABAA receptors are expressed in lower levels and contain less alpha1

subunits where

Seizures in the Neonatal Period

Binding of GABA agonists/modulators to GABAA receptors trigger either influx or efflux of

chloride ions depending on the neuronal equilibrium potential for chloride

Neonatal brain contains more influx transporters (NKCC1) copmared to efflux transporters

(KCC2)

Overall result: chloride accumulation in intracellular chloride

Birth ischemia and hypoxic ischemia also increase NKCC1

Activation of GABAA receptors in neonatal brain causes chloride efflux and neuronal

depolarization

In adult brain, GABAA receptor binding causes influx of chloride into cells, decreasing excitability

In neonatal brain, leads to cessation of outward seizure manifestations, persist electrical seizure

activity

Antiepileptics in Hypothermia

Systematic review has shown that use of AEDs following perinatal asphyxia

in the absence of confirmed seizures is of little benefit with no

improvement in survival or neurodevelopmental outcome

Hypothermia is known to alter the pharmacokinetics of many medications

Data describing PK of AEDs in therapeutic hypothermia are still emerging

Therapeutic Hypothermia and

Pharmacokinetics

Physiologic changes that affect many organ systems

Renal impact

Can alter clearance

Hepatic impact

Altered cytochrome P450 enzyme activity in animal models

Evidence of altered enzyme activity in humans

Morphine in neonates undergoing hypothermia

Can alter metabolism (impact dependent on type of metabolism)

Donovan M et al. Drugs 2016

Treatment for Neonatal Seizures

Goals of therapy:

Cessation or minimization of seizure activity

Minimal to no risk of long-term neurotoxicity

AED efficacy most commonly defined as 80% reduction in seizure severity or complete

seizure cessation

Some combinations of AEDs may cause increased neuronal apoptosis

Phenobarbital

Place in therapy:

First-line AED in neonatal seizures due to extensive history of its use

Mechanism:

Increases GABAA-mediated inhibition

Limited efficacy since GABAA more likely to be excitatory in neonates

Monitoring: serum concentrations

Concerns:

Increased neuronal apoptosis, impaired neurodevelopment

Electroclinical uncoupling/dissociation

Clinically-relevant drug interactions

Population PK of Phenobarbital in Neonatal

HIE treated with Hypothermia

Retrospective evaluation of 39 neonates

TH: 20, normothermic: 19

No difference in PK/levels between the two groups

Body weight, postnatal age were the only predictors of clearance

Clearance of PB increases proportionately with increasing body weight

Dosing recommendation: use same initial dosing as non-HIE neonates,

adjust maintenance dose based on levels

Shelhaas RA et al. Pediatr Crit Care Med 2013

Effect of Co-Medication on PK Parameters

of Phenobarbital in Asphyxiated Newborns

Prospective open-label study in term asphyxiated newborns (GA >37 wk) with HIE and treated with phenobarbital

Standardized phenobarbital dosing

Load: 10-20 mg/kg/dose over 15 min

Maintenance 2.5-4 mg/kg IV twice daily

Repeat loading dose up to 40 mg/kg total

Non-responders:

Phenytoin (15-20 mg/kg IV, 2.5-4 mg/kg IV twice daily maintenance)

Midazolam 0.05-0.3 mg/kg continuous infusion

Phenobarbital levels asses at 2-3, 24, 48, 72, and 96 hr after load

Sima M. et al Physiol Res 2015



Co-medications considered in analysis:

Vasoactives: dopamine, dobutamine, norepinephrine

AEDs: phenytoin, midazolam

Analgesics: sufentanil, tramadol

Diuretics: furosemide

Possible dose-dependent and dose-independent interactions between PB and other

medications evaluated

Dose-dependent: cumulative doses of co-medication within acute phase of treatment used

(normalized to kg of body weight)

Dose-independent: any dosing/exposure to co-medication



Possible mechanistic pathways for PK interactions

Alteration of renal blood flow after vasoactive medications

Changes in clearance

Changes in body water content induced by diuretics

Changes in volume of distribution

Alterations in elimination due to alterations in liver drug metabolism

Changes in half-life, clearance



37 full term newborns enrolled

Patient Demographics Number

Male, n (%) 22 (59%)

Hypothermia, n (%) 24 (65%)

Normothermia, n (%) 13 (35%)

Gestational age (wk) 39.32 + 1.36

Body weight (kg) 3.24 + 0.65

PB loading dose 5.04 to 34.29 mg/kg

PB maintenance dose 1.07 to 20.31 mg/kg/day


of Phenobarbital in Asphyxiated NewbornsVd (L/kg) Cl (L/hr/kg) T ½ (h)

All patients 0.48 0.0034 93.7

Any vasoactive

drug

Yes

No

0.47

0.48

0.0034

0.0043

93.02

93.7

Norepinephrine

Yes

No

0.44

0.48

0.0052

0.0034

62.8

92.4

Phenytoin

Yes

No

0.45

0.48

0.0034

0.0035

128.3

92.4

Furosemide

Yes

No

0.48

0.45

0.0034

0.0035

92.4

93.7

Phenytoin

Mechanism:

Reduces excitatory neurotransmission by blocking voltage-gated sodium

channels

Place in therapy: 2nd line to phenobarbital

Efficacy only 50% when used in combination with phenobarbital

Monitoring: serum concentrations (free and total)

Concerns:

Potential detrimental effect on developing neurons

Phenytoin in Hypothermia

Data specifically describing use of phenytoin for neonatal HIE patients

undergoing hypothermia are lacking

Hypothermia reduces elimination via reduced cytochrome P450 2C

metabolism

Pediatric therapeutic hypothermia data suggests that phenytoin

clearance is significantly decreased

Increased drug levels for extended period of time after cooling

Trends towards higher free levels during rewarming

Close monitoring of serum concentrations warranted

Empey PE et al. Crit Care Med 2013

Lidocaine

Mechanism:

Inhibits voltage-gated sodium channels, preventing depolarization

Place in therapy:

Second or third-line agent

Dosing formulation: IV only (continuous)

Efficacy up to 78%

Monitoring:

Serum concentrations (>9 mg/L results in toxicity)

Lidocaine

Safety Concerns:

Cardiotoxicity—proarrhythmias and bradycardia

Seen in some normothermic infants receiving lidocaine

Clearance:

“High clearance” –strongly dependent on hepatic blood flow

Decreased during hypothermia secondary to decreased cardiac output, stroke volume

Lidocaine PK-PD in Hypothermia

Cardiotoxicity mechanism

Serum concentration

Heart rate

TH could theoretically decrease risk of toxicity compared to normothermic

HIE infants

Heart rate reduced by hypothermia itself

Lidocaine in Asphyxiated Newborn

with Hypothermia

Severe perinatal asphyxia followed by

encephalopathy qualifying for TH

TH started within 6 hours of birth and maintained

x 72 hours

Comparison group-historical controls

(normothermic asphyxiated neonates with

seizures)

Van den Broek et al. Arch Dis Child Fetal Neonatal Ed 2013


with Hypothermia

Intervention:

Lidocaine started when seizures persisted on aEEG despite phenobarbital and

midazolam therapy

Empirically decreased dosing for predicted decrease in clearance

2 mg/kg over 10 min, 4 mg/kg/hr x 6 hours, 2 mg/kg/hr 6-12 hours

Monitoring:

Levels obtained daily


with Hypothermia

Efficacy:

>80% reduction in seizure burden within 4 hours of starting infusion

Safety:

Assessed using cardiac monitoring

Clinical monitoring of arrhythmias based on observation of sudden deviations in

heart frequency


with Hypothermia

22 asphyxiated term neonates undergoing hypothermia who received

lidocaine for seizures

Serum concentrations: 83

Efficacy:

20/22 (91%) of neonates responded to addition of lidocaine

2 neonates who did not respond had severe structural brain damage on MRI

Safety:

No effect of lidocaine plasma concentrations on heart rate

No arrhythmias were observed


with Hypothermia

Figure 2 Relationships between lidocaine and heart rate.

Time-course of the heart rate (HF, upper) and the heart

rate change from baseline (dHF, lower) during lidocaine

infusion under hypothermia. Lines represent the median

and the minimum and maximum observed values.

Lidocaine Proposed Dosing Algorithm

After loading infusion:

• 5.9% of the simulated newborns had a concentration >9 mg/L

• 2.2% of simulated newborns with concentrations >10 mg/L

• 2.5% had a plasma concentration below 4 mg/l

Midazolam (Benzodiazepines)

Place in therapy: 2nd or 3rd line

Mechanism:

Increase inhibitor neurotransmission via GABAA receptor

Efficacy 50% as second-line agent, 73-100% as third-line agent

Dosing formulation: IV (intermittent, continuous), PO

Monitoring: none

Concerns:

Higher doses can cause cardiac depression

Serum concentrations can build up with decreased hepatic function

Benzodiazepines may cause neurodevelopmental impairment, smaller hippocampal

region in brain

Levetiracetam

Place in therapy: 2nd or 3rd line

Mechanism:

Thought to work via stabilization of synaptic vesicles to prevent release of

neuroexcitatory transmitters

Dosing formulation: IV or PO (1:1 conversion)

Monitoring: serum concentrations available, no clear data to support

Efficacy 35-64% in first 24 hours, 52-100% within 72 hours

Concerns:

Relatively safe, does not cause neuronal apoptosis

Somnolence, irritability seen in pediatric patients

Levetiracetam For the Treatment of

Seizures in Neonatal HIE

Study objective: determine the safety and efficacy of levetiracetam in treatment of

neonatal seizures due to HIE

Single-center retrospective cohort at Cincinnati Children’s

Neonates treated with hypothermia for HIE between August 2008-April 2015

GA>35 weeks

Clinical recognized encephalopathy or seizures

One of the following: fetal distress at delivery, resuscitation, 5 min APGAR<6, metabolic acidosis

(pH<7.1 or base deficit>10)

Venkatesan C. et al. J of child neurol 2017



Additional criteria applied for cooling

Physiologic criteria:

Cord blood gas or any postnatal gas at < 1 hour of life with a pH < 7.0 or a base

deficit of > 16

If no blood gas available or blood gas had pH 7.01-7.15 and/or base deficit 10-

15.9 AND history of acute perinatal event AND 10 min AGPAR <10 OR need for

continuous ventilation initiated at birth and continued for at least 10 min

Neurologic criteria:

Presence of moderate/severe encephalopathy OR seizures

TH eligibility: criteria recognized, initiated within 6 hours of birth



EEG monitoring

Continuous prolonged video EEG completed in most neonates

4/32 (12%) levetiracetam patients had treatment initiated at outside hospitals with incomplete records upon transfer or inability to monitor via continuous EEG

Neonatal seizure protocol

If seizures persist: pyridoxine challenge, midazolam continuous infusion, Fosphenytoin, or other AEDs

Once loading dose initiated of an AED, patients placed on maintenance doses

Phenobarbital 20 mg/kg x1

Phenobarbital 20 mg/kg x 1

Levetiracetam 50 mg/kg x 1





Cooled: 87

Not cooled: 40



*Seizure cessation occurred after initiation, no additional AEDs required

Neonates-Levetiracetam N = 32

Prolonged (>24 hr) continuous EEG, n (%) 28 (88)

Seizure cessation after initiation, n (%) 27 (84)

LEV used as 2nd line agent to phenobarbital* 23 (72)

Mean dosing time between PB and LEV 6 hr (1-15 hours)

Time to seizure cessation (LEV 2nd line to PB) 72 hr of seizure

onset

LEV used 3rd line, n (%)* 2 (6)

LEV used 1st line, n (%)* 2 (6)



5 (16%) failed levetiracetam initiation

N = 1: LEV 50 mg/kg x 3PB 20 mg/kgTOP 5 mg/kg

N = 1: PBLEVFOSTOPmidazolam drip

N = 3: PBLEVFOS

Cessation of seizures generally occurred 48 hours after first PB dose



Dosing information

Total loading dose (mg/kg) 63 (range: 20-150 mg/kg)

Initial loading dose (mg/kg) 50 mg/kg

Maintenance dose (mg/kg/day) 65 (range: 30-100)

Maintenance dose at discharge

(mg/kg/day)

58 (range: 5-100)

Maintenance dose divided BID, n (%) 17 (56)

Discharged home on LEV, n (%) 20 (63)

Age at discontinuation 4.4 months (range: 21 days-8.7

months)

Duration of follow-up 32 months (range: 2-64)

Topiramate

Mechanism:

Reduces frequency of action potential firing by altering GABA neurotransmission,

blocking voltage-gated sodium channels, weakly blocking glutamate receptors

Place in therapy: emerging 3rd line option

Effectiveness: 67%

Dosing formulation: PO only (may give rectally)

Monitoring: None

Concerns:

Appears well-tolerated

Potentially neuroprotective, reduces brain injury in HIE models (glutamate blockade)

Potentially additive neuronal apoptosis when co-administered with phenobarbital

Topirimate Neuroprotection Data

Neuronal cultures:

Consistently attenuates cell damage induced by oxygen-glucose deprivation

or excitotoxic glutamate concentrations

Animal models of transient global cerebral ischemia

Reduced severity of tissue damage when used alone or in combination with

hypothermia

Neuroprotective doses: 5-200 mg/kg, usually single dose

Animal models of neonatal periventricular leukomalacia

Exerts neuroprotective effects

Safety and Efficacy of Topirimate in

Neonates with HIE (NeoNATI)

Study objective: evaluate the safety of TOP 10 mg/kg (higher dose than previous study of 5 mg/kg) and its long-term effect on neurologic functions

Multicenter randomized controlled pilot trial of newborns treated with whole body hypothermia within 6 hours from birth

GA > 36 weeks and BW > 1.8 kg AND one of the following

10 min A PGAR < 5

Persisting need for resuscitation, including intubation or mask ventilation 10 min after birth

Acidosis (pH <7.0 and/or base deficit > 16

Moderate to severe encephalopathy

Filippi et al. J Matern Fetal Neonatal Med 2017



Fluid management:

60-70 mL/kg/day, increased by 10-20 mL/kg/day based on changes in body weight and serum electrolyte levels

Minimal enteral nutrition allowed with human milk from first day of life

Seizure management:

1st line phenobarbital

2nd line midazolam

Hypotension (MAP<40mmHg):

Saline bolusesdopamine, dobutamine, norepinephrine

Analgesia: fentanyl



Topamax 10 mg/kg/day started from beginning of hypothermia

Daily x 3 days for total of 3 doses

Plasma concentrations

T0: Before beginning drug/hypothermia

T1 and every 4 hours for first 34 hours (trough prior to 2nd dose, peak)

T40, 48, trough prior to 3rd dose, peak

Additional levels obtained at 12, 24, 48 hours after discontinuation of therapy



Safety assessment

Respiratory and hemodynamic paramaters

Before starting hypothermia, q6h x 72 hours then after rewarming

CBC, glucose, electrolytes, LFTs, renal function, cardiac enzymes, CRP, coagulation studies x 96 hours

Outcome measures

Primary: combined frequency of mortality and severe neurodevelopmental delay (18-24 months)

Secondary: epilepsy, blindness, hearing loss, neurodevelopmental delay (composite motor or cognitive score <85, any degree of CP, visual, or hearing impairment)



Neuroimaging follow-up with standard structural brain MRI

End of hypothermia, within first week, and as clinically indicated

Blinded neuroradiologist interpreted MR studies using scoring system to rate extent of injury in the basal ganglia/thalamus region (0-4) and in the watershed region (0-5)

Higher scores corresponded to more extensive damage

MRI classified accorded to predominant pattern of injury

Normal

WS predominant

BG/T predominant



All patients

N=44

H-TOP

N=21

H

N=23P value

Male, n (%) 21 (67.4) 13 (61.9) 14 (60.9) 0.95

GA, wk 39.2 + 1.53 38.8 + 1.32 40.2 + 1.6 0.34

BW, kg 3.3 + 0.497 3.204 + 0.529 3.388 + 0.469 0.22

Outborn, n (%) 43 (97.7) 20 (95.5) 23 (100) 0.3

APGAR, 1 min 1 (0-7) 1 (0-7) 1 (0-7) 0.87

APGAR, 5 min 4 (0-8) 4 (0-7) 4 (0-8) 1

Mechanical ventilation, n (%) 21 (70.5) 14 (66.7) 17 (73.9) 0.55

Tx with phenobarbital for seizures, n (%) 28 (63.6) 14 (66.6) 14 (60.9) 0.7



No significant difference in primary outcome



No significant differences in patient co-treated with TOP and controls for

most hemodynamic parameters

HR significantly lower at T66 and T72

No adverse effects related to TOP were observed

No patient was discontinued early secondary to limiting adverse effects

Summary

HIE remains a significant etiology of neonatal seizures

Therapeutic hypothermia has not altered overall incidence but has caused

changes in seizure burden, duration, and clinical presentation

Developmental differences in the neonatal brain are responsible for

altered responses to traditional antiepileptic drugs compared to older

patient populations

Neonatal pharmacodynamics may demonstrate need for alternative

therapies such as lidocaine, levetiracetam, and topirimate

Further studies are needed to validate potentially neuroprotective

properties of certain antiepileptic agents

Questions

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